Federal Register / Vol. 88, No. 160 / Monday, August 21, 2023 / Notices 56837 

1Section 503B(a) of the FD&C Act. 

2Compare section 503A(a) of the FD&C Act (21 

U.S.C. 353a(a) (exempting drugs compounded in 

accordance with that section)) with section 503B(a) 

of the FD&C Act (not providing an exemption from 

CGMP requirements). 3Section 503B(b)(4) and (5) of the FD&C Act. 

Proposed Project 

National Surveillance of Community 

Water Systems and Corresponding 

Populations with the Recommended 

Fluoridation Level (OMB Control No. 

0920–1319, Exp. 2/29/2024)— 

Extension—National Center for Chronic 

Disease Prevention and Health 

Promotion (NCCDPHP), Centers for 

Disease Control and Prevention (CDC). 

Background and Brief Description 

Community water fluoridation is the 

process of adjusting the fluoride 

concentration of a community water 

system (CWS) to the level beneficial for 

prevention of dental caries as 

recommended by the U.S. Public Health 

Service (PHS). Community water 

fluoridation is a major factor 

contributing to the large decline in 

caries in the U.S. in the past 75 years 

and is recognized as one of 10 great 

public health achievements of the 

twentieth century. Community water 

fluoridation reduces dental caries by 

25% and is a safe and the cost-effective 

way to deliver fluoride to people of all 

ages, regardless of education and 

income level. It is especially important 

for populations with limited access to 

preventive dental measures. 

CDC is authorized to collect the 

information under the U.S. Public 

Health Service Act. This data collection 

aligns with CDC’s strategy to use public 

health surveillance to inform programs 

and policies to improve the oral health 

of the nation by reducing disparities and 

expanding access to effective prevention 

programs. CDC uses the Water 

Fluoridation Reporting System (WFRS) 

to collect water fluoridation coverage 

and quality throughout the U.S. This 

data allows CDC and States to monitor 

the performance and efficiency of their 

water fluoridation programs, which will 

improve and extend program delivery. 

Respondents to the information 

collection are State fluoridation 

managers or other State government 

officials designated by the State dental 

director or drinking water administrator. 

State participation in the data collection 

is voluntary. 

CDC requests OMB approval for an 

estimated 2,824 annual burden hours. 

There is no cost to respondents other 

than their time to participate. 

ESTIMATED ANNUALIZED BURDEN HOURS

Type of respondents Form name Number of 

respondents 

Number of 

responses per 

respondent 

Average 

burden per 

response 

(in hours) 

Total burden 

(in hours) 

State Official ...................................... Fluoridation status and population ... 50 1 38 1,900 

State Official ...................................... Fluoride testing data ........................ 33 1 28 924 

Total ........................................... ........................................................... ........................ ........................ ........................ 2,824 

Jeffrey M. Zirger, 

Lead, Information Collection Review Office, 

Office of Public Health Ethics and 

Regulations, Office of Science, Centers for 

Disease Control and Prevention. 

[FR Doc. 2023–17925 Filed 8–18–23; 8:45 am] 

BILLING CODE 4163–18–P 

DEPARTMENT OF HEALTH AND 

HUMAN SERVICES 

Food and Drug Administration 

[Docket No. FDA–2018–N–3240] 

List of Bulk Drug Substances for 

Which There is a Clinical Need Under 

Section 503B of the Federal Food, 

Drug, and Cosmetic Act 

AGENCY: Food and Drug Administration, 

HHS. 

ACTION: Notice. 

SUMMARY: The Food and Drug 

Administration (FDA, the Agency, or 

we) is evaluating substances that have 

been nominated for inclusion on a list 

of bulk drug substances (active 

pharmaceutical ingredients) for which 

there is a clinical need (the 503B Bulks 

List). Drug products that outsourcing 

facilities compound using bulk drug 

substances on the 503B Bulks List can 

qualify for certain exemptions from the 

Federal Food, Drug, and Cosmetic Act 

(FD&C Act) provided certain conditions 

are met. This notice identifies two bulk 

drug substances that FDA has 

considered and is not including on the 

list at this time: ephedrine sulfate and 

hydroxychloroquine sulfate. Additional 

bulk drug substances nominated by the 

public for inclusion on this list are 

currently under consideration and will 

be the subject of future notices. 

DATES: The announcement of the notice 

is published in the Federal Register on 

August 21, 2023. 

ADDRESSES: For access to the docket to 

read background documents or the 

electronic and written/paper comments 

received, go to https://

www.regulations.gov and insert the 

docket number, found in brackets in the 

heading of this document, into the 

‘‘Search’’ box and follow the prompts, 

and/or go to the Dockets Management 

Staff, 5630 Fishers Lane, Rm. 1061, 

Rockville, MD 20852, 240–402–7500. 

FOR FURTHER INFORMATION CONTACT: 

Tracy Rupp, Center for Drug Evaluation 

and Research, Food and Drug 

Administration, 10903 New Hampshire 

Ave., Bldg. 51, Silver Spring, MD 20993, 

301–796–3100. 

SUPPLEMENTARY INFORMATION: 

I. Background 

Section 503B of the FD&C Act (21 

U.S.C. 353b) describes the conditions 

that must be satisfied for drug products 

compounded in an outsourcing facility 

to be exempt from section 505 (21 

U.S.C. 355) (concerning the approval of 

drugs under new drug applications 

(NDAs) or abbreviated new drug 

applications (ANDAs)), section 502(f)(1) 

(21 U.S.C. 352(f)(1)) (concerning the 

labeling of drugs with adequate 

directions for use), and section 582 of 

the FD&C Act (21 U.S.C. 360eee–1) 

(concerning drug supply chain security 

requirements).1

Compounded drug products that meet 

the conditions set forth in section 503B 

are not exempt from current good 

manufacturing practice (CGMP) 

requirements in section 501(a)(2)(B) of 

the FD&C Act (21 U.S.C. 351(a)(2)(B)).2

Outsourcing facilities are also subject to 

FDA inspections according to a riskbased schedule, adverse event reporting 

requirements, and other conditions that 

help to mitigate the risks of the drug 

products they compound.3 Outsourcing 

facilities may or may not obtain 

prescriptions for identified individual 

patients and can, therefore, distribute 

compounded drugs to healthcare 


ddrumheller on DSK120RN23PROD with NOTICES1
56838 Federal Register / Vol. 88, No. 160 / Monday, August 21, 2023 / Notices 

4Section 503B(d)(4)(C) of the FD&C Act. 

5Section 503B(a)(2)(A) of the FD&C Act. 

6Section 503B(a)(2)(A)(i)(I) to (III) of the FD&C 

Act. 

7See Federal Register of August 28, 2018 (83 FR 

43877), March 4, 2019 (84 FR 7383), September 3, 

2019 (84 FR 46014), July 31, 2020 (85 FR 46126), 

March 24, 2021 (86 FR 15673), November 23, 2022 

(87 FR 71642), and April 6, 2023 (88 FR 20531). The 

comment period for the July 2020 notice was 

reopened for 30 days on January 8, 2021 (86 FR 

1515), to allow interested parties an additional 

opportunity to comment. FDA has not yet reached 

a final determination on whether each of the 

substances evaluated in the September 2019, July 

2020, or March 2021 notices will be added to the 

503B Bulks List. In addition, bumetanide, which 

was considered in the August 2018 notice, remains 

under consideration by the Agency. 

8See section 503B(a)(2) of the FD&C Act, which 

defines bulk drug substances used in compounding 

under section 503B according to 21 CFR 207.3(a)(4) 

‘‘or any successor regulation.’’ 21 CFR 207.1 is the 

successor regulation. 

9Section 503B(a)(2) of the FD&C Act and 21 CFR 

207.1. 

10 Inactive ingredients are not subject to section 

503B(a)(2) of the FD&C Act and will not be 

included in the 503B Bulks List because they are 

not included within the definition of a bulk drug 

substance. Pursuant to section 503B(a)(3), inactive 

ingredients used in compounding must comply 

with the standards of an applicable U.S. 

Pharmacopeia (USP) or National Formulary (NF) 

monograph, if a monograph exists. 

11This is consistent with procedures set forth in 

section 503B(a)(2)(A)(i) of the FD&C Act. Although 

the statute only directs FDA to issue a Federal 

Register notice and seek public comment when it 

proposes to include bulk drug substances on the 

503B Bulks List, we intend to seek comment when 

the Agency has evaluated a nominated substance 

and proposes either to include or not to include the 

substance on the list. 

12Section 503B of the FD&C Act does not require 

FDA to consult the PCAC before developing the 

503B Bulks List. 

13 In January 2017, FDA announced the 

availability of a revised final guidance for industry 

that provides additional information regarding 

FDA’s policies for bulk drug substances nominated 

for the 503B Bulks List pending FDA’s evaluation 

under the ‘‘clinical need’’ standard, entitled 

‘‘Interim Policy on Compounding Using Bulk Drug 

Substances Under Section 503B of the Federal 

Food, Drug, and Cosmetic Act’’ (the ‘‘Interim 

Policy’’), available at https://www.fda.gov/media/ 

94402/download. We update guidances 

periodically. For the most recent version of a 

guidance, check the FDA guidance web page at 

https://www.fda.gov/regulatory-information/searchfda-guidance-documents. 

practitioners for ‘‘office stock,’’ to hold 

in their offices in advance of patient 

need.4

One of the conditions that must be 

met for a drug product compounded by 

an outsourcing facility to qualify for the 

exemptions under section 503B of the 

FD&C Act is that the outsourcing facility 

may not compound a drug using a bulk 

drug substance unless: (1) the bulk drug 

substance appears on a list established 

by the Secretary of Health and Human 

Services (the Secretary) identifying bulk 

drug substances for which there is a 

clinical need (the 503B Bulks List) or (2) 

the drug compounded from the bulk 

drug substance appears on the drug 

shortage list in effect under section 506E 

of the FD&C Act (21 U.S.C. 356e) at the 

time of compounding, distribution, and 

dispensing.5

Section 503B of the FD&C Act directs 

FDA to establish the 503B Bulks List by: 

(1) publishing a notice in the Federal 

Register proposing bulk drug substances 

to be included on the list, including the 

rationale for such proposal; (2) 

providing a period of not less than 60 

calendar days for comment on the 

notice; and (3) publishing a notice in the 

Federal Register designating bulk drug 

substances for inclusion on the list.6

FDA has published a series of Federal 

Register notices addressing bulk drug 

substances nominated for inclusion on 

the 503B Bulks List.7 This notice 

identifies two bulk drug substances that 

FDA has considered and is not 

including on the 503B Bulks List. 

For purposes of section 503B of the 

FD&C Act, bulk drug substance means 

an active pharmaceutical ingredient as 

defined in 21 CFR 207.1.8 Active 

pharmaceutical ingredient means any 

substance that is intended for 

incorporation into a finished drug 

product and is intended to furnish 

pharmacological activity or other direct 

effect in the diagnosis, cure, mitigation, 

treatment, or prevention of disease, or to 

affect the structure or any function of 

the body, but the term does not include 

intermediates used in the synthesis of 

the substance.9 10

II. Methodology for Developing the 

503B Bulks List 

A. Process for Developing the List 

FDA requested nominations for 

specific bulk drug substances for the 

Agency to consider for inclusion on the 

503B Bulks List in the Federal Register 

of December 4, 2013 (78 FR 72838). FDA 

reopened the nomination process in the 

Federal Register of July 2, 2014 (79 FR 

37747) and provided more detailed 

information on what FDA needs to 

evaluate nominations for the list. On 

October 27, 2015 (80 FR 65770), the 

Agency opened a new docket, FDA– 

2015–N–3469, to provide an 

opportunity for interested persons to 

submit new nominations of bulk drug 

substances, renominate substances with 

sufficient information, or submit 

comments on nominated substances. 

As FDA evaluates bulk drug 

substances, it intends to publish notices 

for public comment in the Federal 

Register that describe its proposed 

position on each substance along with 

the rationale for that position.11 After 

considering any comments on FDA’s 

proposals regarding whether to include 

nominated substances on the 503B 

Bulks List, FDA intends to consider 

whether input from the Pharmacy 

Compounding Advisory Committee 

(PCAC) on the nominations would be 

helpful to the Agency in making its 

determination, and if so, it will seek 

PCAC input.12 Depending on its review 

of the docket comments and other 

relevant information before the Agency, 

FDA may finalize its proposed 

determination without change, or it may 

finalize a modification to its proposal to 

reflect new evidence or analysis 

regarding clinical need. FDA will then 

publish in the Federal Register a final 

determination identifying the bulk drug 

substances for which it has determined 

there is a clinical need and FDA’s 

rationale in making that final 

determination. FDA will also publish in 

the Federal Register a final 

determination regarding those 

substances it considered but found that 

there is no clinical need to use in 

compounding and FDA’s rationale in 

making this decision. 

FDA intends to maintain a list of all 

bulk drug substances it has evaluated on 

its website and separately identify bulk 

drug substances it has placed on the 

503B Bulks List and those it has decided 

not to place on the 503B Bulks List. This 

list is available at https://www.fda.gov/ 

media/120692/download. FDA will only 

place a bulk drug substance on the 503B 

Bulks List when it has determined there 

is a clinical need for outsourcing 

facilities to compound drug products 

using the bulk drug substance. If a 

clinical need to compound drug 

products using the bulk drug substance 

has not been demonstrated, based on the 

information submitted by the nominator 

and any other information considered 

by the Agency, FDA will not place a 

bulk drug substance on the 503B Bulks 

List. 

FDA is evaluating bulk drug 

substances nominated for the 503B 

Bulks List on a rolling basis. FDA 

intends to evaluate and publish in the 

Federal Register the proposed and final 

determinations in groups of bulk drug 

substances until all nominated 

substances that were sufficiently 

supported have been evaluated and 

either placed on the 503B Bulks List or 

identified as bulk drug substances that 

were considered but determined not to 

be appropriate for inclusion on the 503B 

Bulks List.13

B. Analysis of Substances Nominated 

for the List 

As noted above, the 503B Bulks List 

will include bulk drug substances for 

which there is a clinical need. The 


ddrumheller on DSK120RN23PROD with NOTICES1
Federal Register / Vol. 88, No. 160 / Monday, August 21, 2023 / Notices 56839 

14 In March 2019, FDA announced the availability 

of a final guidance entitled ‘‘Evaluation of Bulk 

Drug Substances Nominated for Use in 

Compounding Under Section 503B of the Federal 

Food, Drug, and Cosmetic Act’’ (the ‘‘Clinical Need 

Guidance’’), available at https://www.fda.gov/ 

media/121315/download. This guidance describes 

FDA policies for developing the 503B Bulks List 

and the Agency’s interpretation of the phrase ‘‘bulk 

drug substances for which there is a clinical need’’ 

as it is used in section 503B. The analysis under 

the statutory ‘‘clinical need’’ standard described in 

this notice is consistent with the approach 

described in FDA’s guidance. 

15See 84 FR 46014. 

16FDA made a final determination not to include 

dipyridamole on the 503B Bulks List (see 87 FR 

4240). FDA made a final determination not to 

include methacholine chloride and sodium 

bicarbonate on the 503B Bulks List (see 88 FR 

20531). 

17 86 FR 15673. 

18 88 FR 20531. 

Agency is evaluating bulk drug 

substances that were nominated for 

inclusion on the 503B Bulks List, 

proceeding case by case, under the 

standard provided by the statute.14 In 

applying this standard to make its 

determinations regarding the substances 

set forth in this notice, FDA interprets 

the phrase ‘‘bulk drug substances for 

which there is a clinical need’’ to mean 

that the 503B Bulks List may include a 

bulk drug substance if: (1) there is a 

clinical need for an outsourcing facility 

to compound the drug product and (2) 

the drug product must be compounded 

using the bulk drug substance. FDA 

does not interpret supply issues, such as 

backorders, to be within the meaning of 

‘‘clinical need’’ for compounding with a 

bulk drug substance. Section 503B of 

the FD&C Act separately provides for 

compounding from a bulk drug 

substance under the exemptions from 

the FD&C Act discussed above if the 

drug product compounded from the 

bulk drug substance is on the FDA drug 

shortage list at the time of 

compounding, distribution, and 

dispensing. Additionally, FDA does not 

consider convenience in administering a 

particular compounded drug product 

(e.g., a ready-to-use form) or the cost of 

the compounded drug product as 

compared with an FDA-approved drug 

product when assessing ‘‘clinical need.’’ 

Both bulk drug substances addressed 

in this notice, ephedrine sulfate and 

hydroxychloroquine sulfate, are 

components of FDA-approved drug 

products. FDA therefore began its 

evaluation by asking one or both, as 

applicable, of the following questions: 

1. Is there a basis to conclude, for 

each FDA-approved product that 

includes the nominated bulk drug 

substance, that (a) an attribute of the 

FDA-approved drug product makes it 

medically unsuitable to treat certain 

patients for a condition that FDA has 

identified for evaluation, and (b) the 

drug product proposed to be 

compounded is intended to address that 

attribute? 

2. Is there a basis to conclude that the 

drug product proposed to be 

compounded must be produced from a 

bulk drug substance rather than from an 

FDA-approved drug product? 

The reason for question 1 is that 

unless an attribute of the FDA-approved 

drug is medically unsuitable for certain 

patients, and a drug product to be 

compounded using a bulk drug 

substance that is a component of the 

FDA-approved drug is intended to 

address that attribute, there is no 

clinical need to compound a drug 

product using that bulk drug substance. 

Rather, such compounding would 

unnecessarily expose patients to the 

risks associated with drug products that 

do not meet the standards applicable to 

FDA-approved drug products for safety, 

effectiveness, quality, and labeling and 

would undermine the drug approval 

process. The reason for question 2 is 

that to place a bulk drug substance on 

the 503B Bulks List, FDA must 

determine that there is a clinical need 

for outsourcing facilities to compound a 

drug product using the bulk drug 

substance rather than starting with an 

FDA-approved drug product. When it is 

feasible to compound a drug product by 

starting with an FDA-approved drug 

product, there are certain benefits of 

doing so over starting with a bulk drug 

substance, including that FDA-approved 

drugs have undergone premarket review 

for safety, effectiveness, and quality, 

and are manufactured by a facility that 

is subject to premarket assessment, 

including site inspection, as well as 

routine post-approval risk-based 

inspections. In contrast, FDA does not 

conduct a premarket review of the 

quality standards, specifications, and 

controls for bulk drug substances used 

in compounding and does not conduct 

a premarket assessment of the 

manufacturer of the bulk drug 

substance. 

If the answer to both of the above 

questions is ‘‘yes,’’ there may be a 

clinical need for outsourcing facilities to 

compound using the bulk drug 

substance, and we would evaluate the 

substance further, applying the factors 

described below. If the answer to either 

of these questions is ‘‘no,’’ we generally 

would not include the bulk drug 

substance on the 503B Bulks List, 

because there would not be a basis to 

conclude that there may be a clinical 

need to compound drug products using 

the bulk drug substance instead of 

administering an FDA-approved drug or 

compounding starting with an FDAapproved drug product. FDA did not 

answer ‘‘yes’’ to both of the threshold 

questions for the two bulk drug 

substances that are components of FDAapproved drug products that we are 

addressing in this notice. Accordingly, 

as explained below, we did not proceed 

further in our evaluation of these 

substances and have decided not to 

include them on the 503B Bulks List. 

III. FDA’s Determinations Regarding 

Substances Proposed for the 503B Bulks 

List 

The two bulk drug substances that 

FDA has evaluated, proposed not to 

include on the 503B Bulks List in a 

Federal Register notice, and has now 

decided not to place on the 503B Bulks 

List are ephedrine sulfate (Refs. 1 and 2) 

and hydroxychloroquine sulfate (Ref. 3). 

In September 2019, the Agency issued 

a Federal Register notice in which it 

evaluated nine nominated bulk drug 

substances under the section 503B 

statutory standard—dipyridamole, 

ephedrine sulfate, famotidine, 

hydralazine HCl, methacholine 

chloride, sodium bicarbonate, sodium 

tetradecyl sulfate, trypan blue, and 

vecuronium bromide—and proposed 

not to include them on the 503B Bulks 

List (the September 2019 notice).15 In 

the present notice, after review of the 

comments submitted to the docket for 

the September 2019 notice, FDA is 

making its final determination not to 

include ephedrine sulfate on the 503B 

Bulks List. At this time, FDA is not 

making a final determination regarding 

famotidine, hydralazine HCl, sodium 

tetradecyl sulfate, trypan blue, and 

vecuronium bromide.16 These 

substances remain under consideration 

by FDA. 

In March 2021, the Agency issued a 

Federal Register notice in which it 

evaluated five nominated bulk drug 

substances under the section 503B 

statutory standard (the March 2021 

notice).17 FDA proposed to include 

quinacrine hydrochloride (for oral use 

only) on the 503B Bulks List. FDA 

proposed not to include bromfenac 

sodium, mitomycin-C, nepafenac, and 

hydroxychloroquine sulfate on the 503B 

Bulks List. In April 2023, after review of 

comments submitted to the March 2021 

docket, the Agency issued a Federal 

Register notice, making its final 

determination to include quinacrine 

hydrochloride on the 503B Bulks List to 

compound drug products for oral use 

only.18 In the present notice, after 

review of the comments submitted to 

the docket for the March 2021 notice, 

FDA is making its final determination 


ddrumheller on DSK120RN23PROD with NOTICES1
56840 Federal Register / Vol. 88, No. 160 / Monday, August 21, 2023 / Notices 

19See Docket No. FDA–2013–N–1524, document 

nos. FDA–2013–N–1524–2292 and FDA–2013–N– 

1524–2298. 

20Nominator(s) proposed to compound a 

preservative-free solution. However, they failed to 

acknowledge that there is a preservative-free 

formulation of ephedrine sulfate that is marketed or 

explain why that formulation would be medically 

unsuitable for certain patients. Additionally, since 

the September 2019 notice, ephedrine sulfate has 

been FDA-approved as a preservative-free, 25 mg/ 

5mL (5 mg/mL) single dose, premixed, labeled 

syringe (not for dilution) (See NDA 213407 labeling 

available as of the date of this notice at https://

www.accessdata.fda.gov/spl/data/3155f177-4aff4560-9f7c-f77649d065d9/3155f177-4aff-4560-9f7cf77649d065d9.xml) and a preservative-free, 50 mg/ 

10mL (5 mg/mL) single dose, premixed vial (See 

NDA 213407 labeling available as of the date of this 

notice at https://www.accessdata.fda.gov/spl/data/ 

54276f21-7800-44f4-ae51-0060fb1c43ad/54276f21- 

7800-44f4-ae51-0060fb1c43ad.xml). 

21See Docket No. FDA–2018–N–3240, document 

no. FDA–2018–N–3240–0047. Other commenters 

proposed additional uses and routes of 

administration: intramuscular administration of a 

higher concentration of ephedrine sulfate for 

postoperative nausea and vomiting refractory to 

traditional antiemetics; intravenous or intrathecal 

administration of ephedrine sulfate for hypotension 

in patients that received a certain type of anesthesia 

or received an overdose of a drug that can lower 

blood pressure; and continuous (intravenous) 

infusion to prevent hypotension secondary to spinal 

anesthesia during cesarean section. These other 

uses will not be considered further because the 

commenters either proposed uses or routes of 

administration already evaluated in the September 

2019 notice and the literature provided in the 

comments did not contain any new information that 

would support FDA’s reconsideration of its 

proposal on the substance, or the commenters 

proposed new uses or routes of administration but 

did not provide sufficient information, including 

citations to relevant literature, supporting a clinical 

need. 

22See, e.g., NDAs 208943 and 208289. 

23See, e.g., NDAs 208289 and NDA 213407. 

24See Docket No. FDA–2018–N–3240, document 

nos. FDA–2018–N–3240–0043, FDA–2018–N– 

3240–0045, FDA–2018–N–3240–0050, FDA–2018– 

N–3240–0052. 

25See Docket No. FDA–2018–N–3240, document 

no. FDA–2018–N–3240–0047. 

26 In noting this issue, we do not mean to suggest 

or imply that the approved drug products, or 

products prepared from them, are approved for the 

use proposed by the commenter. For the Part 1.a. 

analysis we asked a limited, threshold question to 

determine whether there might be clinical need for 

a compounded drug product, by asking what 

attributes of the FDA-approved drug the proposed 

compounded drug would change, and why. Because 

this proposed product did not pass through Part 1.a. 

(for the reasons described in the memo) we did not 

reach Part 2 and therefore did not consider the Part 

2 factors, including the available evidence of 

effectiveness or lack of effectiveness of a drug 

product compounded with ephedrine sulfate. FDAapproved ephedrine sulfate 50 mg/mL solution for 

dilution has not been shown to be safe and effective 

for intracorporal administration to treat priapism. 

27The commenter proposes that in order to 

achieve a 100 mg/mL dose, more than one vial of 

FDA-approved ephedrine sulfate is needed. While 

there is a 50 mg/mL formulation that is available 

in 1 mL vials, there is also an FDA-approved 

formulation of intravenous ephedrine sulfate 

solution that is available as a 500 mg/10 mL vial 

(dilution required). In order to achieve the 100 mg/ 

mL dose, 2 mL of ephedrine sulfate could be used. 

not to include hydroxychloroquine 

sulfate on the 503B Bulks List. At this 

time, FDA is not making a final 

determination regarding bromfenac 

sodium, mitomycin-C, and nepafenac. 

These substances remain under 

consideration by FDA. 

Because both ephedrine sulfate and 

hydroxychloroquine sulfate are 

components of FDA-approved drug 

products, FDA considered one or both 

of the following questions: (1) is there 

a basis to conclude that an attribute of 

each FDA-approved drug product 

containing the bulk drug substance 

makes each one medically unsuitable to 

treat certain patients for a condition that 

FDA has identified for evaluation, and 

the drug product(s) proposed to be 

compounded is intended to address that 

attribute in each FDA-approved drug 

product and (2) is there a basis to 

conclude that the drug product(s) 

proposed to be compounded must be 

compounded using a bulk drug 

substance. FDA considered comments to 

the docket submitted within the public 

comment period, but as explained 

below, none of the comments received 

on these bulk drug substances provided 

information that led FDA to change its 

determination. 

A. Ephedrine Sulfate 

Ephedrine sulfate was nominated for 

inclusion on the 503B Bulks List to 

compound drug products to treat acute 

bronchospasm, drug induced 

hypotension due to anesthesia, and 

nasal congestion.19 The proposed route 

of administration is intravenous, the 

proposed dosage form is a preservativefree solution, and the proposed 

strengths are 5 mg/mL and 10 mg/mL.20

During the comment period for the 

September 2019 notice, a commenter 

proposed that there was a clinical need 

to compound higher concentration 

ephedrine sulfate drug products to treat 

priapism. The proposed route of 

administration for this new proposed 

use is intracorporeal, the proposed 

dosage form is a solution, and the 

proposed strength is 100 mg/mL.21

Because additional references were 

provided supporting this proposed use 

and route of administration, FDA 

considered this use and this route of 

administration before reaching a final 

clinical need determination (Ref. 2). 

As noted above, ephedrine sulfate is 

a component of FDA-approved drug 

products (e.g., NDAs 208943 and 

208289). FDA-approved ephedrine 

sulfate is available as a 1 mL single-dose 

drug product that contains 50 mg/mL 

(50 mg/mL) ephedrine sulfate, 

preservative-free, for intravenous 

administration, and as a 10 mL multidose vial that contains 500 mg/10 mL 

(50 mg/mL) ephedrine sulfate, with 

preservative, for intravenous 

administration.22 These ephedrine 

sulfate drug products must be diluted 

before administration to achieve the 

desired concentration for their labeled 

indications. Ephedrine sulfate is also 

available as a 5 mL single dose, prefilled 

syringe that contains 25 mg/5 mL (5 mg/ 

mL) ephedrine sulfate, preservative-free, 

for intravenous administration, and as a 

10 mL single dose, prefilled syringe that 

contains 50 mg/10 mL (5 mg/mL) 

ephedrine sulfate, preservative-free, for 

intravenous administration.23 The 

products available as prefilled syringes 

are premixed formulations and do not 

require dilution prior to administration 

for their labeled indications. 

1. Suitability of FDA-Approved Drug 

Product 

In its proposal to not include 

ephedrine sulfate on the 503B Bulks 

List, FDA explained that the 

nominations did not identify an 

attribute of the FDA-approved drug 

products that make them medically 

unsuitable to treat certain patients and 

that the proposed compounded drug 

products are intended to address. 

Several comments received agreed with 

FDA’s proposal not to include 

ephedrine sulfate on the 503B Bulks 

List.24 Several comments were not 

supportive. However, none of the 

comments received on FDA’s proposal 

provided information that led FDA to 

change its position on this question. A 

commenter stated that there is a clinical 

need for an intracorporeal, singleingredient, higher concentration 

ephedrine sulfate compounded drug 

product for use to treat priapism.25

However, the commenter failed to 

identify an attribute of the FDAapproved drug products, including the 

intravenous formulations of ephedrine 

sulfate 50 mg/mL solution for dilution 

(e.g., NDA 208943), that is medically 

unsuitable for patients with priapism or 

identify an attribute of the FDAapproved products that the proposed 

compounded drug product is intended 

to address. The FDA-approved products 

are available in the concentration of 50 

mg/mL (undiluted) and can be 

administered in a sufficient volume or 

in multiple doses to achieve the 

proposed dose of 100 mg for the 

treatment of priapism.26 27 A commenter 

also stated that the FDA-approved 

ephedrine sulfate products are not 

compatible with new technology such 

as syringe-robotics and vial docking 

technology to easily make stock 


ddrumheller on DSK120RN23PROD with NOTICES1
Federal Register / Vol. 88, No. 160 / Monday, August 21, 2023 / Notices 56841 

28See Docket No. FDA–2018–N–3240, document 

no. FDA–2018–N–3240–0047. 

29See footnote 20 above. 

30See Docket No. FDA–2018–N–3240, document 

nos. FDA–2018–N–3240–0053, FDA–2018–N– 

3240–0049, and FDA–2018–N–3240–0047. 

31See Docket No. FDA–2015–N–3469, document 

no. FDA–2015–N–3469–0165. 

32See, e.g., NDA 009768 labeling available as of 

the date of this notice at https://

www.accessdata.fda.gov/drugsatfda_docs/label/ 

2017/009768s037s045s047lbl.pdf. 

33See, e.g., ANDA 040104 labeling available as of 

the date of this notice at https://

www.accessdata.fda.gov/spl/data/e5375cf7-9423- 

40a4-bd33-ce5812da4a73/e5375cf7-9423-40a4- 

bd33-ce5812da4a73.xml. 

34See, e.g., ANDA 213342 labeling available as of 

the date of this notice at https://

www.accessdata.fda.gov/spl/data/a594d892-e496- 

38f5-e053-2a95a90a9da8/a594d892-e496-38f5- 

e053-2a95a90a9da8.xml. 

35See, e.g., NDA 009768 labeling available as of 

the date of this notice at https://

www.accessdata.fda.gov/drugsatfda_docs/label/ 

2017/009768s037s045s047lbl.pdf. 

36 In noting this issue, we do not mean to suggest 

or imply that the approved drug products, or 

products prepared from them, are approved for all 

of the uses proposed by the nomination. For the 

question 1 analysis we asked a limited, threshold 

question to determine whether there might be a 

clinical need for a compounded drug product, by 

asking what attributes of the approved drug the 

proposed compounded drug would change, and 

why. Because this nomination did not pass through 

question 2, we did not reach the balancing test and 

therefore did not consider the four factors, 

including the available evidence of effectiveness or 

lack of effectiveness of a drug product compounded 

with hydroxychloroquine sulfate. The safety and 

efficacy of chronic use of hydroxychloroquine 

sulfate have not been established for juvenile 

idiopathic arthritis. 

37We note that the nominator’s proposed 

concentration of 100 to 200 mg/mL would offer 

little benefit in the younger aged pediatric 

population because a suspension at this strength 

would likely require administration of small 

volumes (e.g., ≤1 mL). We are aware of several 

published pharmacy compounding formulations for 

hydroxychloroquine sulfate 25 mg/mL suspensions 

(Refs. 4 to 6), which may be more suitable for the 

younger pediatric population. 

solutions to produce onsite.28 However, 

FDA is not aware of issues with using 

the FDA-approved product when the 

compounding process and equipment 

are appropriately selected. Additionally, 

these arguments do not take into 

account the approval by FDA of two 

ephedrine sulfate drug products that are 

pre-diluted and thus would not need 

additional manipulation at the bedside 

by a medical provider before use for 

their labeled indications.29 Commenters 

also made various arguments addressing 

supply issues, convenience, and cost.30

However, as explained above, FDA does 

not consider supply issues, 

convenience, and costs to be within the 

meaning of ‘‘clinical need’’ for 

compounding with a bulk drug 

substance under section 503B of the 

FD&C Act. Accordingly, with respect to 

the ephedrine sulfate drug products 

proposed to be compounded, FDA finds 

no basis to conclude that an attribute of 

the FDA-approved product makes it 

medically unsuitable to treat certain 

patients for a condition that FDA has 

identified for evaluation. 

2. Whether the Drug Product Must Be 

Compounded From a Bulk Drug 

Substance 

The nominations do not provide 

support for the position that drug 

products containing ephedrine sulfate 

must be compounded from bulk drug 

substances rather than the approved 

drug product. No further information 

was supplied during the comment 

period that supports the need for 

compounding ephedrine sulfate drug 

products from bulk drug substances. 

Because there is no basis to conclude 

that an attribute of the FDA-approved 

ephedrine sulfate products makes them 

medically unsuitable for some patients; 

however, FDA has not considered 

whether there is a basis to conclude that 

the proposed compounded products 

must be made from a bulk drug 

substance rather than from an FDAapproved product. 

B. Hydroxychloroquine Sulfate 

Hydroxychloroquine sulfate was 

nominated for inclusion on the 503B 

Bulks List to compound drug products 

to treat rheumatoid arthritis and 

juvenile arthritis (also known as 

juvenile idiopathic arthritis).31 The 

proposed route of administration is oral, 

the proposed dosage forms are a capsule 

or suspension, and the proposed doses 

or concentrations are 200 to 500 mg 

capsules and 100 to 200 mg/mL 

suspension. The nominated bulk drug 

substance is a component of FDAapproved drug products (e.g., NDA 

009768, ANDA 040104, and ANDA 

213342).32 33 34

FDA-approved hydroxychloroquine 

sulfate is available as 200 mg 

(equivalent to 155 mg of 

hydroxychloroquine base), film-coated 

tablets for oral administration.35

1. Suitability of FDA-Approved Drug 

Product(s) 

As described in FDA’s preliminary 

Federal Register notice addressing this 

substance, there is a basis to conclude 

that an attribute of the approved 

hydroxychloroquine sulfate tablets for 

oral administration makes them 

medically unsuitable for the treatment 

of some patients with rheumatoid 

arthritis and juvenile arthritis.36 The 

nomination suggested that the FDAapproved oral tablets, a solid oral 

dosage form, are medically unsuitable in 

pediatric patients who are unable to 

swallow tablets. We agree that there 

may be certain patients for whom the 

approved oral tablets are medically 

unsuitable, and this would depend on a 

patient’s clinical presentation and age, 

among other considerations. As a 

general matter, the drug product 

proposed to be compounded appears to 

address the potential unsuitability of a 

solid oral dosage form because the 

nominator proposes to compound a 

suspension of hydroxychloroquine 

sulfate for oral administration. 

The nomination further states that 

‘‘pediatric dosing is not standardized 

but weight-based, making getting the 

correct dose difficult with tablets.’’ We 

agree that an oral suspension could 

allow for more flexible dosing when 

compared to the approved tablets when 

following weight-based dosing 

recommendations, and that this also 

supports the proposition that the 

approved product may be unsuitable for 

certain patients.37

In addition to the proposed 

suspension, the nomination also 

proposes that there is a clinical need to 

compound hydroxychloroquine sulfate 

200 to 500 mg capsules for oral 

administration. The nomination does 

not explain how the proposed 

compounded capsule products are 

intended to address the medical 

unsuitability of the approved product. 

Similar to tablets, capsules are less 

flexible in dosing and would be difficult 

for patients to take if they are unable to 

swallow tablets. In addition, the 

nomination does not identify any data 

or information as to the need for 

compounded products with a higher 

concentration than the approved 

product. No further information was 

supplied on this point during the 

comment period. 

The nomination also claims that some 

patients are ‘‘unable to tolerate 

excipients’’ in the approved product, 

but the nomination does not identify 

which excipients they are referring to, 

nor do they provide any data or 

information supporting how the 

proposed drug products will address 

that particular attribute. No further 

information was supplied on this point 

during the comment period. 

2. Whether the Drug Product Must Be 

Compounded From a Bulk Drug 

Substance 

Because there is a basis to conclude 

that an attribute of the approved 

hydroxychloroquine sulfate tablets 

makes them medically unsuitable for 

some patients, and the proposed 

compounded oral suspension is 

intended to address that attribute, FDA 


ddrumheller on DSK120RN23PROD with NOTICES1
56842 Federal Register / Vol. 88, No. 160 / Monday, August 21, 2023 / Notices 

38The tablet is not scored. The approved product 

labeling states that the ‘‘film-coated tablets cannot 

be divided, therefore they should not be used to 

treat patients who weigh less than 31 kg.’’ 

39We note that the product labeling for 

hydroxychloroquine sulfate film-coated tablets (e.g., 

NDA 009768, ANDA 213342) states, ‘‘Do not crush 

or divide hydroxychloroquine sulfate film-coated 

tablets.’’ However, this does not change our view 

that the product can be compounded starting with 

the approved drug product. 

40See 84 FR 7390, which is available at https:// 

www.federalregister.gov/documents/2019/03/04/ 

2019-03807/evaluation-of-bulk-drug-substancesnominated-for-use-in-compounding-under-section503b-of-the. 

41See Public Law 113–54, section 102(a) (2013), 

which is available at https://www.govinfo.gov/ 

content/pkg/PLAW-113publ54/pdf/PLAW113publ54.pdf. 

42See United States v. Evers, 643 F.2d 1043, 1048 

(5th Cir. 1981) (‘‘[W]hile the [FD&C Act] was not 

intended to regulate the practice of medicine, it was 

obviously intended to control the availability of 

drugs for prescribing by physicians.’’); United 

States v. Regenerative Scis., LLC, 741 F.3d 1314, 

1319–20 (D.C. Cir. 2014); (citing Evers and noting 

that the FD&C Act ‘‘regulate[s] the distribution of 

drugs by licensed physicians’’); Gonzales v. Raich, 

545 U.S. 1, 28 (2005) (‘‘[T]he dispensing of new 

drugs, even when doctors approve their use must 

await federal approval.’’). 43Athenex Inc. v. Azar, 397 F. Supp. 3d 56, 72 

(D.D.C. 2019). 44Section 503B(a)(2(A)(i) and (ii) of the FD&C 

Act. 

next considers whether there is a basis 

to conclude that the proposed oral 

suspension must be made from a bulk 

drug substance rather than from an 

FDA-approved product. The approved 

hydroxychloroquine sulfate drug 

products are 200 mg immediate release 

tablets with film coating.38

As described in FDA’s preliminary 

Federal Register notice addressing this 

substance, although the approved 

products are film-coated, the coating is 

not intended to change/control the 

release profile. FDA is not aware of 

issues with using the FDA-approved 

product when the compounding process 

and equipment are appropriately 

selected. No further information was 

supplied on this point during the 

comment period. We also note that there 

is a draft USP monograph for the 

compounded suspension that uses an 

FDA-approved film-coated tablet as the 

starting material (Ref. 6).39 As with all 

suspensions, the particle size of the 

powder should be carefully controlled 

and the density of suspension vehicle 

should be selected appropriately in 

order to make the oral suspension 

uniform and stable, which can affect the 

dose administrated to the patients. 

One commenter supported FDA’s 

proposal not to include 

hydroxychloroquine sulfate on the 503B 

Bulks List. Commenters provided no 

new information supporting the clinical 

need for compounding from the bulk 

drug substance hydroxychloroquine 

sulfate. Because we do not find a basis 

to conclude that a bulk drug substance 

is needed to compound the proposed 

compounded hydroxychloroquine 

sulfate oral suspension, rather than 

starting with the FDA-approved 

product, we do not find a clinical need 

to include hydroxychloroquine sulfate 

on the 503B Bulks List under question 

2. 

IV. Other Issues Raised in Nominations 

and Comments 

Commenters expressed concern that 

nominations submitted before FDA 

issued the Clinical Need Guidance in 

March 2019 are disadvantaged in 

demonstrating clinical need because the 

nominators might not have fully 

understood FDA’s thinking on clinical 

need when they submitted their 

nominations.40 In addition, there was 

also concern expressed about whether 

FDA is evaluating bulk drug substances 

for clinical need pursuant to a nonbinding guidance document. 

FDA disagrees with these comments. 

First, as explained in section II.B of this 

notice, FDA is evaluating bulk drug 

substances nominated for inclusion on 

the 503B Bulks List under the ‘‘clinical 

need’’ standard provided by the FD&C 

Act, as amended by the Drug Quality 

and Security Act in 2013.41 The analysis 

under the statutory ‘‘clinical need’’ 

standard described in this notice is 

consistent with the approach described 

in FDA’s Clinical Need Guidance. 

Second, there have been many 

opportunities for nominators and 

interested members of the public to 

provide information supporting a 

clinical need to compound drug 

products containing the bulk drug 

substances that are the subject of this 

notice. As explained in section II.A, a 

public docket, FDA–2015–N–3469, is 

available for interested persons to 

submit nominations, including updated 

or revised nominations, or comments on 

nominated substances. Furthermore, 

during the comment periods for the 

September 2019 and March 2021 

Federal Register notices, commenters 

had an additional opportunity to submit 

comments to the docket associated with 

those notices to provide additional 

supporting information for the bulk 

drug substances that are the subject of 

this notice, and many did so. 

Another issue raised was whether 

FDA is regulating and interfering with 

the practice of medicine by not placing 

bulk drug substances on the 503B Bulks 

List despite some physicians wanting to 

prescribe drug products compounded 

from those bulk drug substances. FDA 

disagrees with these comments. The 

Agency’s evaluation under the clinical 

need standard only regulates the ability 

of certain compounded drug products to 

reach the market and is well within the 

Agency’s authorities.42 The Agency is 

fulfilling its statutory mandate of 

regulating outsourcing facilities’ 

production and distribution of 

compounded drug products, not 

interfering with physicians’ clinical 

decisions regarding which drug 

products to prescribe. Indeed, a Federal 

court considered the very claim raised 

in these comments and determined that 

FDA’s evaluation under the clinical 

need standard ‘‘regulates the type of 

drug that reaches the marketplace,’’ a 

decision that ‘‘rests well within FDA’s 

regulatory authority under the [FD&C 

Act] . . . and . . . does not intrude on 

the practice of medicine.’’ 43

Another concern was the possibility 

that FDA is promoting the off-label use 

of FDA-approved drug products. FDA 

disagrees that it is promoting the offlabel use of FDA-approved drug 

products. In performing the clinical 

need evaluation, FDA asks a limited, 

threshold question to determine 

whether there might be a clinical need 

for a compounded drug product, by 

asking what attributes of the approved 

drug product the proposed compounded 

drug product would change and why. 

Asking this question helps ensure that 

if a bulk drug substance is included on 

the 503B Bulks List, it is to compound 

drug products that include a needed 

change to an approved drug product, 

rather than to compound drug products 

without such a change. We do not 

suggest that the approved drug product 

or products prepared from it are 

approved for the use proposed by the 

nomination being evaluated. 

Regarding FDA’s decision to evaluate 

clinical need in the context of the 

specific drug products proposed to be 

compounded in the nomination, a 

concern was raised that requiring 

nominators to provide information on 

specific drug products is unnecessary to 

determine whether there is a clinical 

need for the bulk drug substance and 

that FDA should not evaluate bulk drug 

substances in the context of finished 

dosage forms for drug products. FDA 

disagrees with these comments. As 

explained in section I of this notice, 

section 503B of the FD&C Act limits the 

bulk drug substances that outsourcing 

facilities can use in compounding to 

those that are used to compound drugs 

in shortage or that appear on a list 

developed by FDA of bulk drug 

substances for which there is a clinical 

need.44 Section 503B of the FD&C Act 

includes this limitation, among others, 


ddrumheller on DSK120RN23PROD with NOTICES1
Federal Register / Vol. 88, No. 160 / Monday, August 21, 2023 / Notices 56843 

45By contrast, to qualify for the exemptions in 

section 503A of the FD&C Act, drug products 

compounded by licensed pharmacists in Statelicensed pharmacies or Federal facilities, or by 

licensed physicians, must be compounded based on 

the receipt of a valid prescription for an 

individually identified patient. This means that for 

drug products compounded under section 503A, to 

meet the conditions of that section and qualify for 

the exemptions in the statute, the pharmacist or 

physician compounding under section 503A of the 

FD&C Act must compound either: (1) after receiving 

a valid prescription for an identified, individual 

patient or (2) before receiving a patient-specific 

prescription, in limited quantities, based on a 

history of receiving valid orders generated solely 

within the context of an established relationship 

with the patient or prescriber. See FDA’s final 

guidance for industry ‘‘Prescription Requirement 

Under Section 503A of the Federal Food, Drug, and 

Cosmetic Act’’ (December 2016). 

46For drug products compounded under section 

503A of the FD&C Act to meet the conditions of that 

section and qualify for the exemptions in the 

statute, drug products must be compounded in a 

State: (i) that has entered into a memorandum of 

understanding with the Secretary which addresses 

the distribution of inordinate amounts of 

compounded drug products interstate and provides 

for appropriate investigation by a State agency of 

complaints relating to compounded drug products 

distributed outside such State; or (ii) that has not 

entered into the memorandum of understanding 

described in clause (i) and the licensed pharmacist, 

licensed pharmacy, or licensed physician 

distributes (or causes to be distributed) 

compounded drug products out of the State in 

which they are compounded in quantities that do 

not exceed 5 percent of the total prescription orders 

dispensed or distributed by such pharmacy or 

physician (see section 503A(b)(3)(a)(B)(i) and (ii) of 

the FD&C Act). See also FDA Guidance for Industry, 

‘‘Prescription Requirement Under Section 503A of 

the Federal Food, Drug, and Cosmetic Act,’’ 

December 2016 (available at https://www.fda.gov/ 

media/97347/download). 

47Licensed pharmacies and physicians who 

compound drugs under the conditions of section 

503A of the FD&C Act, including the requirement 

to compound drugs only pursuant to a prescription 

for an identified individual patient, may use many 

bulk drug substances by operation of the statute, 

without action by FDA. See section 

503A(b)(1)(A)(i)(I) and (II) of the FD&C Act 

(providing that a drug product may be compounded 

consistent with the exemptions in section 503A of 

the FD&C Act if the licensed pharmacist or licensed 

physician compounds the drug product using bulk 

drug substances that comply with the standards of 

an applicable USP or NF monograph, if a 

monograph exists, and the USP chapter on 

pharmacy compounding; or if such a monograph 

does not exist, are drug substances that are 

components of drugs approved by the Secretary). 

48Athenex Inc., 397 F. Supp. 3d at 65. 

49 Id. 

to help ensure that outsourcing facilities 

do not grow into conventional 

manufacturing operations making 

unapproved new drug products without 

complying with critical requirements, 

such as new drug approval. Outsourcing 

facilities, as opposed to other 

compounders, may compound and 

distribute drug products for ‘‘office 

stock’’ without first receiving a 

prescription for an individually 

identified patient 45 and without 

conditions on interstate distribution that 

are applicable to other compounded 

drugs.46 Because of these differences 

and others, section 503B of the FD&C 

Act places different conditions on drugs 

compounded by outsourcing facilities, 

including limitation on the outsourcing 

facilities’ use of bulk drug substances, 

which are more stringent than those 

placed on other compounders’ use of 

bulk drug substances.47 The clinical 

need standard in section 503B of the 

FD&C Act requires FDA to perform a 

sorting function—to distinguish bulk 

drug substances for which there is a 

clinical need from those for which there 

is not—and this requires FDA to apply 

its expertise to consider whether there 

is a need for the finished drug product 

that would be compounded from the 

bulk drug substance. Indeed, a Federal 

court considered the very claim raised 

in these comments and determined that 

‘‘[o]nly when ‘clinical need’ is assessed 

against the availability and suitability of 

an approved drug does the term perform 

the classifying function that Congress 

intended.’’ 48 In reaching this view, the 

court found that only when the clinical 

need evaluation ‘‘considers the actual 

way in which the active pharmaceutical 

ingredient supplies a therapeutic 

benefit—by its administration as a 

finished drug product—does the inquiry 

produce the categorization that Congress 

surely envisioned’’ in enacting section 

503B of the FD&C Act.49 FDA’s clinical 

need assessments help limit patient 

exposure to compounded drug products 

that have not been demonstrated to be 

safe and effective to those situations in 

which the compounded drug product is 

necessary for patient treatment. In 

addition, FDA’s assessments preserve 

the incentives for applicants to invest in 

the research and testing required to 

obtain FDA approval and continue to 

manufacture FDA-approved drug 

products, thereby helping to maintain a 

supply of high-quality, safe, and 

effective drugs. 

Finally, changes to the Interim Policy 

were requested. These comments are 

outside the scope of FDA’s bulk drug 

substance evaluations and decisions 

that are the subject of this notice. FDA 

welcomes public comments on its 

guidance documents that address 

human drug compounding. Comments 

on the Interim Policy may be submitted 

to the docket for the guidance, Docket 

No. FDA–2015–D–3539, at any time at 

https://www.regulations.gov. 

V. Conclusion 

For the reasons stated above, we find 

that there is no clinical need for 

outsourcing facilities to compound 

using the bulk drug substances 

ephedrine sulfate and 

hydroxychloroquine sulfate, and 

therefore we are not including these 

bulk drug substances on the 503B Bulks 

List. 

VI. References 

The following references marked with 

an asterisk (*) are on display at the 

Dockets Management Staff (see 

ADDRESSES) and are available for 

viewing by interested persons between 

9 a.m. and 4 p.m., Monday through 

Friday; they are also available 

electronically at https://

www.regulations.gov. References 

without asterisks are not on public 

display at https://www.regulations.gov 

because they have copyright restriction. 

Some may be available at the website 

address, if listed. References without 

asterisks are available for viewing only 

at the Dockets Management Staff. FDA 

has verified the website addresses, as of 

the date this document publishes in the 

Federal Register, but websites are 

subject to change over time. 

*1. FDA Memorandum to File, ‘‘Clinical 

Need for Ephedrine Sulfate in Compounding 

Under Section 503B of the FD&C Act,’’ March 

2021. 

*2. FDA Memorandum to File, ‘‘Clinical 

Need Supplemental Memorandum for 

Ephedrine Sulfate in Compounding Under 

Section 503B of the FD&C Act,’’ August 2023. 

*3. FDA Memorandum to File, ‘‘Clinical 

Need for Hydroxychloroquine Sulfate in 

Compounding Under Section 503B of the 

FD&C Act,’’ March 2021. 

4. McHenry, A.R., M.F. Wempe, and P.J. 

Rice, (2017) ‘‘Stability of Extemporaneously 

Prepared Hydroxychloroquine Sulfate 25-mg/ 

mL Suspensions in Plastic Bottles and 

Syringes,’’ International Journal of 

Pharmaceutical Compounding, 21(3), 251– 

254 (APA). Retrieved from https://ijpc.com/ 

Abstracts/Abstract.cfm?ABS=4322. 

5. American Society of Hospital 

Pharmacists (ASHP 2020), 

‘‘Hydroxychloroquine Sulfate Suspension 25 

mg/mL.’’ Retrieved from www.ashp.org. 

6. USP 2020, ‘‘USP Draft Compounded 

Preparation Monograph for 

Hydroxychloroquine Sulfate Compounded 

Oral Suspension.’’ Published for public 

comment in Pharmacopeial Forum 46(2). 

Retrieved from https://go.usp.org/l/323321/ 

2020-04-08/33wcg6. 

Dated: August 15, 2023. 

Lauren K. Roth, 

Associate Commissioner for Policy. 

[FR Doc. 2023–17881 Filed 8–18–23; 8:45 am] 

BILLING CODE 4164–01–P 


ddrumheller on DSK120RN23PROD with NOTICES1